MaryO

Key takeaways:

• Relacorilant reduced systolic and diastolic BP for adults with Cushing’s syndrome and hypertension.
• Adults with hyperglycemia had reductions in HbA1c and mean glucose at 22 weeks with relacorilant.

Adults with endogenous Cushing’s syndrome had reductions in blood pressure and glucose at 22 weeks of treatment with a selective cortisol modulator, according to topline results from the open-label portion of the GRACE phase 3 trial.

Relacorilant (Corcept Therapeutics) is a medication currently under investigation for multiple disorders, including Cushing’s syndrome and ovarian, adrenal and prostate cancer. The phase 3 GRACE trial included two parts, the first of which was an open-label portion in which 152 adults with Cushing’s syndrome and either hypertension, hyperglycemia or both received relacorilant for 22 weeks. Participants who achieved prespecified improvements for either symptom were invited to the trial’s randomized double-blind withdrawal phase in which adult were randomly assigned, 1:1, to relacorilant or placebo for 12 weeks. The topline results announced by Corcept Therapeutics are only from the open-label portion of the trial.

Relacorilant improved symptoms of hypertension and hyperglycemia among adults with Cushing's syndrome. Image: Adobe Stock

All adults with hypertension had a rapid decrease in systolic and diastolic BP at 6 weeks that was maintained through the end of the open-label phase. At 22 weeks, participants with hypertension had a 7.9 mm Hg decrease in systolic BP and a 5.4 mm Hg decline in diastolic BP (P < .0001 for both). Of adults with hypertension, 63% met the study’s response criteria. Adults who entered the randomized withdrawal phase had a 12.6 mm Hg improvement in systolic BP and an 8.3 mm Hg decrease in diastolic BP from baseline to 22 weeks (P < .0001 for both).

Adults with hyperglycemia included those with diabetes and people with impaired glucose tolerance. The hyperglycemia group had improvements in multiple measures of glucose metabolism from baseline to 22 weeks. Mean HbA1c declined by 0.3 percentage points and mean fasting glucose decreased by 12.4 mg/dL from baseline to 22 weeks (P = .03 for both). Mean glucose area under the curve also declined from baseline to 22 weeks (P < .0001). Half of adults with hyperglycemia met the study’s response criteria. Adults who enrolled in the randomized portion of the trial had a reduction in HbA1c of 0.7 percentage points (P < .0001) and fasting glucose of 25.2 mg/dL (P = .006) from baseline to 22 weeks. Glucose AUC also declined at 22 weeks (P < .0001).

Relacorilant was deemed well tolerated in the trial. The most common adverse events were nausea, edema, back and extremity pain and fatigue, all of which were mild or moderate in nature and are consistent with symptoms people experience after surgery or the start of therapy to treat hypercortisolism. No increases in cortisol levels or relacorilant-induced hypokalemia were observed. There were no cases of relacorilant-induced endometrial hypertrophy with or without vaginal bleeding, adrenal insufficiency or QT prolongation

Richard Auchus

“These open-label results are compelling, and they provide important information about the treatment of hypercortisolism,” Richard Auchus, MD, PhD, professor of internal medicine in the division of metabolism, endocrinology and diabetes at the University of Michigan and chief of the endocrinology and metabolism section at the Ann Arbor VA Medical Center, said in a press release. “Patients showed marked improvement across a broad range of signs and symptoms, without significant safety burden. Due to relacorilant’s unique mechanism of action, we are not observing other toxicities seen with current therapies, which positions relacorilant to potentially become a new standard of care for patients with this disease.”

Corcept Therapeutics plans to present data on both the open-label and randomized withdrawal phases of the trial in June and submit a new drug application to the FDA in the second quarter of this year.

From https://www.healio.com/news/endocrinology/20240422/investigational-cushings-syndrome-medication-reduces-bp-glucose-in-openlabel-trial?utm_source=selligent&utm_medium=email&utm_campaign=news

Hmmm - the images that somehow aren't showing up:

Meanwhile...

Choose wisely...

http://cushieblog.files.wordpress.com/2012/04/maryo-colorful-zebra1.gif

~~~~~~~~~

For this year, anyone remember Karnac from Johnny Carson?  I hold in my hand...?  And the cued audience starts cheering, seemingly delighted that this is the last question?
 

For me, I hold in my hand the last post for this year.  I hope the audience isn't cheering but I am.  Sharing or re-sharing these posts another year is getting to be a PITA and I'm not sure anyone is even reading them.

Maybe next year I won't do them again.  Maybe next year there won't be these message boards.  Maybe...

And today, we talk about pink jeeps and ziplines...

How in the world did we get here in a Cushing's Challenge?  I'm sliding these in because earlier I linked (possibly!) my growth hormone use as a cause of my cancer - and I took the GH due to Cushing's issues.  Clear?  LOL

http://cushieblog.files.wordpress.com/2012/04/pink-jeep.jpg?w=300&h=225

I had found out that I had my kidney cancer on Friday, April 28, 2006 and my surgery on May 9, 2006.  I was supposed to go on a Cushie Cruise to Bermuda on May 14, 2006.  My surgeon said that there was no way I could go on that cruise and I could not postpone my surgery until after that cruise.

I got out of the hospital on the day that the other Cushies left for the cruise and realized that I wouldn't have been much (ANY!) fun and I wouldn't have had any.

An especially amusing thread from that cruise is The Adventures of Penelopee Cruise (on the Cushing's Help message boards).  Someone had brought a UFC jug and decorated her and had her pose around the ship.

The beginning text reads:

Penelopee had a lovely time on Explorer of the Seas which was a five day cruise to Bermuda. She needed something to cheer her up since her brother, Tom, went off the deep end, but that's another story!

Penelopee wanted to take in all of the sights and sounds of this lovely vessel. Every day she needed to do at least one special thing. Being a Cushie, she didn't have enough spoons to do too much every day.

On the first day, she went sunning on the Libido deck......she didn't last too long, only about 10 minutes. Goodness, look at her color! Do you think maybe her ACTH is too high?

Although I missed this trip, I was feeling well enough to go to Sedona, Arizona in August 2006.  I convinced everyone that I was well enough to go off-road in a pink jeep,  DH wanted to report me to my surgeon but I survived without too much pain and posed for the header image.

In 2009, I figured I had “extra years” since I survived cancer and I wanted to do something kinda scary, yet fun. So, somehow, I decided on ziplining. Tom wouldn’t go with me but Michael would so I set this up almost as soon as we booked a Caribbean cruise to replace the Cushie Cruise to Bermuda.

Each person had a harness around their legs with attached pulleys and carabiners. Women had them on their chests as well. In addition, we had leather construction gloves and hard hats.

We climbed to the top of the first platform and were given brief instructions and off we went. Because of the heavy gloves, I couldn’t get any pictures. I had thought that they would take some of us on the hardest line to sell to us later but they didn't. They also didn’t have cave pictures or T-Shirts. What a missed opportunity!

This was so cool, so much fun. I thought I might be afraid at first but I wasn’t. I just followed instructions and went.

Sometimes they told us to brake. We did that with the right hand, which was always on the upper cable.

After the second line, I must have braked too soon because I stopped before I got to the platform. Michael was headed toward me. The guide on the end of the platform wanted me to do some hand over hand maneuver but I couldn’t figure out what he was saying so he came and got me by wrapping his legs around me and pulling me to the platform.

After that, no more problems with braking!

The next platform was very high – over 70 feet in the air – and the climb up was difficult. It was very hot and the rocks were very uneven. I don’t know that I would have gotten to the next platform if Michael hadn’t cheered me on all the way.

We zipped down the next six lines up to 250-feet between platforms and 85-feet high in the trees, at canopy level. It seemed like it was all over too soon.

But, I did it! No fear, just fun.

Enough of adventures - fun ones like these, and scary ones like transsphenoidal surgery and radical nephrectomy!

Due to the ongoing symptoms of headaches and known pituitary lesion potentially concerning for neurosarcoidosis, the patient was referred to neuroimmunology. MRI brain, and cervical, thoracic and lumbar spine showed a reduction in the size of the known cystic pituitary lesion, with no findings suggestive of intracranial or spinal sarcoidosis, and no abnormal leptomeningeal enhancement. Electromyography demonstrated normal nerve conduction studies.

Two years following adrenalectomy, the patient has weaned off all glucocorticoid replacement with resolution of his symptoms of adrenal insufficiency. His sarcoidosis remains in remission.

All included studies were either case reports (n = 34) or case series (n = 9). Five articles [8, 9, 14-16] also included a literature review and four [8, 10, 11, 17] included cohort studies in addition to the case report/series. Included articles were published from 1981 to 2021 inclusively. These 43 studies identified 83 unique patient cases of new-onset conditions following the remission of Cushing syndrome (see Table 2 for full patient characteristics). In addition to our case, this review includes 84 cases. Most patients were female (n = 72, 85.7%), and the median reported age was 39.5 years old (IQR = 13 years old, range, 16–80 years old).

The most common aetiology of CS was pituitary adenoma (n = 59), followed by adrenal adenoma (n = 20) and adrenal hyperplasia (n = 4). One patient had a pulmonary neuroendocrine tumour secreting ACTH [8]. All patients but two underwent surgical resection for definitive management of CS. One patient underwent medical management alone with pasireotide [18], and the other had resolution of CS secondary to an adrenal adenoma following adrenal haemorrhage after a motorcycle collision [14]. All patients included in our analysis had documented clinical remission of hypercortisolism, and biochemical remission was reported in 67 cases (79.8%).

The most commonly reported de novo conditions following CS remission were thyroid disorders (n = 41, 48.8%), including 34 cases of thyroiditis [9-11, 17-23] and seven cases of Graves disease [8, 9, 21, 24-26]. Rheumatological disorders were the second most commonly reported conditions (n = 22, 26.2%) with cases of sarcoidosis (n = 13) [8, 14, 27-35], systemic lupus erythematosus (n = 2) [9, 36], rheumatoid arthritis (n = 2) [37, 38], seronegative arthritis (n = 2) [37, 39], polymyalgia rheumatica (n = 1) [40], giant cell arteritis (n = 1) [9] and retinal vasculitis (n = 1) [39] (see Figure 3 and Table 3). Further characterisation of thyroid disorders and sarcoidosis is detailed below.

We identified 11 cases of neurological disorders, including idiopathic intracranial hypertension (IIH) (n = 5) [15, 16, 41-43], multiple sclerosis (n = 2) [44, 45], lymphocytic hypophysitis (n = 2) [46, 47], acute disseminated encephalomyelitis (n = 1) [48] and myasthenia gravis (n = 1) [49]. IIH has been associated with both primary adrenal insufficiency and steroid withdrawal [15]. Glucocorticoids are not routinely used as first-line treatment of IIH (due to the risk of rebound intracranial hypertension upon withdrawal); however, three of the five cases included in this review were successfully treated with higher doses of steroids [15, 16, 41]. Given this association, IIH was considered a steroid-responsive condition for the purpose of this review. Acute disseminated encephalomyelitis is a rare autoimmune disease, causing widespread inflammation of the brain and spinal cord, often associated with preceding viral infection or vaccination. However, as first-line treatment for this condition is high dose corticosteroids, we considered it a steroid-responsive condition and was included in this review [50].

Seven dermatological cases were identified in our scoping review including psoriasis (n = 3) [8, 9], rash (n = 3) [8] and angioedema (n = 1) [51].

Gastrointestinal conditions were the least reported (n = 3) with one case of celiac disease [52], one case of primary biliary cirrhosis [8] and one case of sclerosing pancreatocholangitis [53].

The median reported time between the treatment of CS and the onset of symptoms of de novo condition was 4.1 months (IQR = 3.75 months, range, 10 days to 27 years). Most patients (n = 50, 59.5%) were receiving corticosteroids at the time of onset. Only 22 cases (26.2%) explicitly reported a timeline from discontinuation (n = 6) or tapering (n = 16) of corticosteroid dose to the onset of symptoms, with a median time of 1.75 months (IQR = 3 months, range 7 days-7 months). Thirty-nine patients (46.4%) were subsequently treated with corticosteroids (either re-initiated or at an increased dose). Remission or clinical stability of the de novo condition was reported in 66 cases (78.6%), while seven cases (8.3%) remained uncontrolled, and in 11 cases (13.1%), the outcome was not reported. Of the 44 cases where time to remission was reported, the median time was 3 months (IQR = 4.2 months, range 1–24 months).

I first saw a similar image to this one with the saying Life. Be in it at a recreation center when my son was little.  At the time, it was "Duh, of course, I'm in it".

The original image was a couple of males, a couple of females, and a dog walking/running.  No folks in wheelchairs, no older folks, and certainly no zebras.

It would be nice to have everyone out there walking or running but that's not real life, at least in the Cushie world.  It's been a long time since I've really been In My Life - maybe it's time to get back.

A dear friend who had not one, but two forms of cancer was traveling throughout Europe for the first time after her husband's death wrote:

Some final words before I turn in for the night. If there is a spark of desire within you to do something which is not contrary to God's Holy Law, find a way to make it happen. All things are possible and blessings abound for those who love Him. Life is such an adventure. Don't be a spectator - live every single moment for Him and with Him.

Somedays, it's hard even getting up in the morning but I'm trying.  Pre-COVID I took Water Aerobics for People with Arthritis and I actually went to class three times a week.  After COVID, I took the stuff I learned there and did it 3 times a week as part of "water walking" by myself or with my DH.   I got a "part-time" job several years ago and I'm  teaching piano online.  We had plans for a cruise to Norway which COVID made us reschedule for Alaska, which wass to be rescheduled...again.

I've recently started playing the balalaika with an orchestra even though I never even touched one before.

This is the one and only life I'll ever have and I want to make the most of it!

So often during the diagnosis phase of Cushing's I felt lost like this picture - I was walking alone to an unknown place with an unknown future.

My diagnosis was pre-Internet which meant that any information had to be gotten from libraries, bookstores, magazines...or doctors.  In 1983 to 1986 I knew something was terribly wrong but there was no backup from doctors, family or friends.  My first hope was from a magazine (see Day Six)

After I got that first glimmer of hope, it was off to the library to try to understand medical texts.  I would pick out words I did understand - and it was more words each trip.  I made Xerox copies of my findings to read at home and try to digest. (I still have all those old pages!)

All my research led me to Cushing's.

Unfortunately, the research didn't lead me to doctors who could help for several years.  That contributed greatly to the loneliness.  If a doctor says you're not sick, friends and family are going to believe the doctor, not you.  After all, he's the one trained to know what's wrong or find out.

I was so grateful when I finally got into a clinical trial at NIH and was so nice not to be alone with this mystery illness.  I was also surprised to learn, awful as I felt, there were Cushies much worse off than I was.

I am so glad that the Internet is here now helping us all know that we're not alone anymore.

We're all in this together with help, support, research, just being there.  I love this quote from Catherine at http://wheniwasyou.wordpress.com/2012/03/31/wheniwasyou/

Mary, I am delighted to see you here. Cushings - because of the persistent central obesity caused by (we know now) the lack of growth hormone plus the hypothyroidism I was diagnosed with (but for which treatment was ineffective due to my lack of cortisol) - was one of the things I considered as an explanation for my symptoms. Your site was enormously educational and helpful to me in figuring out what might be happening to me. Those other patient testimonies I referred to? Many of them were the bios you posted. Thank you so much for commenting. I am so grateful for the support and encouragement. I really hope that my experiences will help other undiagnosed hypopituitary patients find their way to a diagnosis. I often used to dream that one day I'd get to say to others what was so often said to me: don't give up, there will be an answer. I kept believing in myself because people I hadn't even met believed in me. Now I am finally here and I do hope my story will help others to have faith in their own instincts.

Thanks again. Please do keep in touch.

Catherine

http://cushieblog.files.wordpress.com/2012/04/maryo-colorful-zebra.gif

I'm sorry I can't find more info on this - 

I'm the Director of Communications for my church now and every year on my birthday I share this same post. 

When our new pastor came onboard last summer, he started to have the staff take turns on sharing weekly devotionals.  My first week at this was this hymn.

"As the darkness of evening falls, our thoughts often turn to the ending of things: the day, our tasks, perhaps even our hopes. In these moments, the plea for God to "abide" with us resonates deeply. It's a prayer for His presence to stay with us as light fades, reminding us that even in the growing darkness, we are not alone. God’s presence is a constant source of comfort and stability."

Over the years, we went on several Windjammer Barefoot Cruises.  We liked them because they were small, casual and were fairly easy on the wallet.

They sailed around the Caribbean to a variety of islands, although they sometimes changed itineraries depending on weather, crew, whatever.  One trip we were supposed to go to Saba but couldn't make port.  A lot of people got off at the next port and flew home.

The captains were prone to "Bedtime Stories" which were often more fiction than true but they added to the appeal of the trip.  We didn't care if we missed islands or not - we were just there to sail over the waves and enjoy the ride.

The last trip we took with them was about two years before I started having Cushing's problems.  (You wondered how I was going to tie this together, right?)

The cruise was uneventful, other than the usual mishaps like hitting docks, missing islands and so on.  Until it was a particularly rough sea one day.  I was walking somewhere on deck and suddenly a wave came up over the deck making it very slippery.  I fell and cracked the back of my head on the curved edge of a table in the dining area.  I had the next-to-the-worse headache I have ever had, the worst being after my pituitary surgery. At least after the surgery, I got some morphine.

We asked several doctors later if that hit could have contributed to my Cushing's but doctors didn't want to get involved in that at all.

The Windjammer folks didn't fare much better, either. In October 1998, Hurricane Mitch was responsible for the loss of the s/v Fantome (the last one we were on). All 31 crew members aboard perished; passengers and other crew members had earlier been offloaded in Belize.

The story was recorded in the book The Ship and the Storm: Hurricane Mitch and the Loss of the Fantome by Jim Carrier.  The ship, which was sailing in the center of the hurricane, experienced up to 50-foot (15 m) waves and over 100 mph (160 km/h) winds, causing the Fantome to founder off the coast of Honduras.

"In October 1998, the majestic schooner Fantome came face-to-face with one of the most savage storms in Atlantic history. The last days of the Fantome are reconstructed in vivid and heartbreaking detail through Jim Carrier's extensive research and hundreds of personal interviews. What emerges is a story of courage, hubris, the agony of command, the weight of lives versus wealth, and the advances of science versus the terrible power and unpredictability of nature."

This event was similar to the Perfect Storm in that the weather people were more interested in watching the hurricane change directions than they were in people who were dealing with its effects.

I read this book and I was really moved by the plight of those crew members.

I'll never know if that hit on my head contributed to my Cushing's but I have seen several people mention on the message boards that they had a traumatic head injury of some type in their earlier lives.

In 2021, I had the bestest ever day...

and, surpassing that:

A couple years later and "My Dream Day" is substantially the same but now it would include playing with my grandchildren and, instead of practicing the aerophone, practicing the balalaika.

Today is already not "My Dream Day" since I'm posting this at 4:26 in the morning!

Maybe next year...

Abstract

Introduction

Chronic excessive exposure to glucocorticoids leads to the diverse clinical manifestations of Cushing syndrome (CS), which has an annual incidence ranging from 1.8 to 3.2 cases per million individuals [1]. The syndrome's signs and symptoms are not pathognomonic, and some of its primary manifestations, such as obesity, hypertension, and glucose metabolism alterations, are prevalent in the general population [2], making diagnosis challenging. Endogenous CS falls into 2 categories: adrenocorticotropic hormone (ACTH)-dependent (80%-85% of cases), mostly due to a pituitary adenoma, or ACTH-independent (15%-20% of cases), typically caused by adrenal adenomas or hyperplasia [3]. Cushing disease (CD) represents a specific form of CS, characterized by the presence of an ACTH-secreting pituitary tumor [1]. Untreated CD is associated with high morbidity and mortality compared to the general population [1], with a 50% survival rate at 5 years [2]. However, surgical removal of a pituitary adenoma can result in complete remission, with mortality rates similar to those of the general population [2]. This article aims to highlight the challenges of suspecting and diagnosing CD and to discuss the current management options for this rare condition.

Case Presentation

A 66-year-old woman received a referral to endocrinology for an evaluation of obesity due to right knee arthropathy. During physical examination, she exhibited a body mass index of 34.3 kg/m², blood pressure of 180/100, a history of non-insulin-requiring type 2 diabetes mellitus with glycated hemoglobin (HbA1c) of 6.9% (nondiabetic: < 5.7%; prediabetic: 5.7% to 6.4%; diabetic: ≥ 6.5%) and hypertension. Additionally, the patient complained of proximal weakness in all 4 limbs.

Diagnostic Assessment

Upon admission, densitometry revealed osteoporosis with T scores of −2.7 in the lumbar spine and −2.8 in the femoral neck. Hypercortisolism was suspected due to concomitant arterial hypertension, central obesity, muscle weakness, and osteoporosis. Physical examination did not reveal characteristic signs of hypercortisolism, such as skin bruises, flushing, or reddish-purple striae. Late-night salivary cortisol (LNSC) screening yielded a value of 8.98 nmol/L (0.3255 mcg/dL) (reference value [RV] 0.8-2.7 nmol/L [0.029-0.101 mcg/dL]) and ACTH of 38.1 pg/mL (8.4 pmol/L) (RV 2-11 pmol/L [9-52 pg/mL]). A low-dose dexamethasone suppression test (LDDST) was performed (cutoff value 1.8 mcg/dL [49 nmol/L]), with cortisol levels of 7.98 mcg/dL (220 nmol/L) at 24 hours and 20.31 mcg/dL (560 nmol/L) at 48 hours. Subsequently, a high-dose dexamethasone suppression test (HDDST) was conducted using a dose of 2 mg every 6 hours for 2 days, for a total dose of 16 mg, revealing cortisol levels of 0.0220 nmol/L (0.08 ng/mL) at 24 hours and 0.0560 nmol/L (0.0203 ng/mL) at 48 hours, alongside 24-hour urine cortisol of 0.8745 nmol/L (0.317 ng/mL) (RV 30-145 nmol/24 hours [approximately 11-53 μg/24 hours]) [4].

These findings indicated the presence of endogenous ACTH-dependent hypercortisolism of pituitary origin. Consequently, magnetic resonance imaging (MRI) was requested, but the results showed no abnormalities. Considering ectopic ACTH production often occurs in the lung, a high-resolution chest computed tomography scan was performed, revealing no lesions.

Treatment

Upon reassessment, the MRI revealed a 4-mm adenoma, prompting the decision to proceed with transsphenoidal resection of the pituitary adenoma.

Outcome and Follow-Up

The histological analysis revealed positive staining for CAM5.2, chromogranin, synaptophysin, and ACTH, with Ki67 staining at 1%. At the 1-month follow-up assessment, ACTH levels were 3.8 pmol/L (17.2 pg/mL) and morning cortisol was 115.8621 nmol/L (4.2 mcg/dL) (RV 5-25 mcg/dL or 140-690 nmol/L). Somatomedin C was measured at 85 ng/mL (RV 70-267 ng/mL) and prolactin at 3.5 ng/mL (RV 4-25 ng/mL). At the 1-year follow-up, the patient exhibited a satisfactory postoperative recovery. However, she developed diabetes insipidus and secondary hypothyroidism. Arterial hypertension persisted. Recent laboratory results indicated a glycated hemoglobin (HbA1c) level of 5.4%. Medications at the time of follow-up included prednisolone 5 milligrams a day, desmopressin 60 to 120 micrograms every 12 hours, losartan potassium 50 milligrams every 12 hours, and levothyroxine 88 micrograms a day.

Discussion

CD is associated with high mortality, primarily attributable to cardiovascular outcomes and comorbidities such as metabolic and skeletal disorders, infections, and psychiatric disorders [1]. The low incidence of CD in the context of the high prevalence of chronic noncommunicable diseases makes early diagnosis a challenge [2]. This case is relevant for reviewing the diagnostic approach process and highlighting the impact of the availability bias, which tends to prioritize more common diagnoses over rare diseases. Despite the absence of typical symptoms, a timely diagnosis was achieved.

Once exogenous CS is ruled out, laboratory testing must focus on detecting endogenous hypercortisolism to prevent misdiagnosis and inappropriate treatment [5]. Screening methods include 24-hour urinary free cortisol (UFC) for total cortisol load, while circadian rhythm and hypothalamic-pituitary-adrenal (HPA) axis function may be evaluated using midnight serum cortisol and LNSC [5]. An early hallmark of endogenous CS is the disruption of physiological circadian cortisol patterns, characterized by a constant cortisol level throughout the day or no significant decrease [2]. Measuring LNSC has proven to be useful in identifying these patients. The LNSC performed on the patient yielded a high result.

To assess HPA axis suppressibility, tests such as the overnight and the standard 2-day LDDST [5] use dexamethasone, a potent synthetic corticosteroid with high glucocorticoid receptor affinity and prolonged action, with minimal interference with cortisol measurement [6]. In a normal HPA axis, cortisol exerts negative feedback, inhibiting the secretion of corticotropin-releasing-hormone (CRH) and ACTH. Exogenous corticosteroids suppress CRH and ACTH secretion, resulting in decreased synthesis and secretion of cortisol. In pathological hypercortisolism, the HPA axis becomes partially or entirely resistant to feedback inhibition by exogenous steroids [5, 6]. The LDDST involves the administration of 0.5 mg of dexamethasone orally every 6 hours for 2 days, with a total dose of 4 mg. A blood sample is drawn 6 hours after the last administered dose [6]. Following the LDDST, the patient did not demonstrate suppression of endogenous corticosteroid production.

After diagnosing CS, the next step in the diagnostic pathway involves categorizing it as ACTH-independent vs ACTH-dependent. ACTH-independent cases exhibit low or undetectable ACTH levels, pointing to adrenal origin. The underlying principle is that excess ACTH production in CD can be partially or completely suppressed by high doses of dexamethasone, a response not observed in ectopic tumors [6]. In this case, the patient presented with an ACTH of 38.1 pg/mL (8.4 pmol/L), indicative of ACTH-dependent CD.

Traditionally, measuring cortisol levels and conducting pituitary imaging are standard practices for diagnosis. Recent advances propose alternative diagnostic methods such as positron emission tomography (PET) scans and corticotropin-releasing factor (CRF) tests [7]. PET scans, utilizing radioactive tracers, offer a view of metabolic activity in the adrenal glands and pituitary region, aiding in the identification of abnormalities associated with CD. Unfortunately, the availability of the aforementioned tests in the country is limited.

Once ACTH-dependent hypercortisolism is confirmed, identifying the source becomes crucial. A HDDST is instrumental in distinguishing between a pituitary and an ectopic source of ACTH overproduction [2, 6]. The HDDST involves administering 8 mg of dexamethasone either overnight or as a 2-day test. In this case, the patient received 2 mg of dexamethasone orally every 6 hours for 2 days, totaling a dose of 16 mg. Simultaneously, a urine sample for UFC is collected during dexamethasone administration. The HDDST suppressed endogenous cortisol production in the patient, suggesting a pituitary origin.

In ACTH-dependent hypercortisolism, CD is the predominant cause, followed by ectopic ACTH syndrome and, less frequently, an ectopic CRH-secreting tumor [3, 5]. With the pretest probability for pituitary origin exceeding 80%, the next diagnostic step is typically an MRI of the pituitary region. However, the visualization of microadenomas on MRI ranges from 50% to 70%, requiring further testing if results are negative or inconclusive [5]. Initial testing of our patient revealed no pituitary lesions. Following a pituitary location, ACTH-secreting tumors may be found in the lungs. Thus, a high-resolution chest computed tomography scan was performed, which yielded negative findings. Healthcare professionals must keep these detection rates in mind. In instances of high clinical suspicion, repeating or reassessing tests and imaging may be warranted [3], as in our case, ultimately leading to the discovery of a 4-mm pituitary adenoma.

It is fundamental to mention that the Endocrine Society Clinical Practice Guideline on Treatment of CS recommends that, when possible, all patients presenting with ACTH-dependent CS and lacking an evident causal neoplasm should be directed to an experienced center capable of conducting inferior petrosal sinus sampling to differentiate between pituitary and nonpituitary or ectopic cause [8]. However, in this instance, such a referral was regrettably hindered by logistical constraints.

Regarding patient outcomes and monitoring in CD, there is no consensus on defining remission criteria following tumor resection. Prolonged hypercortisolism results in suppression of corticotropes, resulting in low levels of ACTH and cortisol after surgical intervention. Typically, remission is identified by morning serum cortisol values below 5 µg/dL (138 nmol/L) or UFC levels between 28 and 56 nmol/d (10-20 µg/d) within 7 days after surgical intervention. In our case, the patient's morning serum cortisol was 115.8621 nmol/L (4.2 µg/dL), indicating remission. Remission rates in adults are reported at 73% to 76% in selectively resected microadenomas and at 43% in macroadenomas [8], highlighting the need for regular follow-up visits to detect recurrence.

Following the surgery, the patient experienced diabetes insipidus, a relatively common postoperative occurrence, albeit usually transient [8]. It is recommended to monitor serum sodium levels during the first 5 to 14 days postsurgery for early detection and management. Additionally, pituitary deficiencies may manifest following surgery. In this patient, prolactin levels were compromised, potentially impacting sexual response. However, postoperative somatomedin levels were normal, and gonadotropins were not measured due to the patient's age group, as no additional clinical decisions were anticipated based on those results. Secondary hypothyroidism was diagnosed postoperatively.

Moving forward, it is important to emphasize certain clinical signs and symptoms for diagnosing CD. The combination of low bone mineral density (Likelihood Ratio [LR] +21.33), central obesity (LR +3.10), and arterial hypertension (LR + 2.29) [9] has a higher positive LR than some symptoms considered “characteristic,” such as reddish-purple striae, plethora, proximal muscle weakness, and unexplained bruising [2, 10]. It is essential to give relevance to the signs the patient may present, emphasizing signs that have been proven to have an increased odds ratio (OR) such as osteoporosis (OR 3.8), myopathies (OR 6.0), metabolic syndrome (OR 2.7) and adrenal adenoma (OR 2.4) [9‐11]. The simultaneous development and worsening of these conditions should raise suspicion for underlying issues. Understanding the evolving nature of CD signs highlights the importance of vigilance during medical examinations, prioritizing the diagnostic focus, and enabling prompt initiation of treatment.

Recognizing the overlap of certain clinical features in CS is fundamental to achieving a timely diagnosis.

Learning Points

• CS diagnosis is challenging due to the absence of pathognomonic signs and symptoms and the overlap of features present in many pathologies, such as metabolic syndrome.

• Early detection of CS is crucial, given its association with high morbidity and mortality resulting from chronic exposure to glucocorticoids.

• Recognizing the combination of low bone mineral density, obesity, hypertension, and diabetes as valuable clinical indicators is key in identifying CS.

• Interdisciplinary collaboration is essential to achieve a comprehensive diagnostic approach.

Acknowledgments

We extend our gratitude to Pontificia Universidad Javeriana in Bogotá for providing essential resources and facilities that contributed to the successful completion of this case report. Special acknowledgment is reserved for the anonymous reviewers, whose insightful feedback significantly enhanced the quality of this manuscript during the peer-review process. Their contributions are sincerely appreciated.

Contributors

All authors made individual contributions to authorship. A.B.O. was involved in the diagnosis and management of this patient. M.A.G., J.M.H., and A.B.O. were involved in manuscript drafting and editing. All authors reviewed and approved the final draft.

Funding

This research received no public or commercial funding.

Disclosures

The authors declare that they have no conflicts of interest related to the current study.

Informed Patient Consent for Publication

Signed informed consent could not be obtained from the patient or a proxy but has been approved by the treating institution.

Data Availability Statement

Restrictions apply to the availability of some or all data generated or analyzed during this study to preserve patient confidentiality or because they were used under license. The corresponding author will on request detail the restrictions and any conditions under which access to some data may be provided.

References

Abbreviations

• ACTH

  adrenocorticotropic hormone

• CD

  Cushing disease

• CRH

  corticotropin-releasing hormone

• CS

  Cushing syndrome

• HDDST

  high-dose dexamethasone suppression test

• HPA

  hypothalamic-pituitary-adrenal

• LDDST

  low-dose dexamethasone suppression test

• LNSC

  late-night salivary cortisol

• MRI

  magnetic resonance imaging

• OR

  odds ratio

• RV

  reference value

• UFC

  urinary free cortisol

Another picture that weirdly turned into a link.

Here's the pink jeep:

 http://cushieblog.files.wordpress.com/2012/04/pink-jeep.jpg?w=300&h=225

Still, and always missing you, my friend.

The Super Sue image